The metastasis of prostate cancer to bone is responsible for decreased patient survival, increased pain and mobility difficulties, and decreased quality of life for patients. Despite the serious consequences of bone metastasis, the mechanisms of bone lesion development remain poorly understood. In patients, primary tumors stimulate abnormal bone formation and turnover without visible metastases. In concert, our preliminary data demonstrates that primary prostate cancer tumor growth stimulates bone formation. Thus, there is evidence that prostate cancer can induce changes in bone remodeling prior to the development of metastases. We hypothesize that proteins involved in tumor growth may also stimulate bone turnover and that these proteins may be delivered to the bone environment by circulating platelets. Therefore, we plan to undertake a careful and systematic investigation into the mechanisms of communication between primary tumor growth and bone remodeling. To accomplish this goal we will complete the following specific aims: 1) Investigate the role of platelets in tumor signaling to bone. 2) Elucidate the role of TSP-1 regulating tumor growth on bone turnover. 3) Study the role of TGF-21 activation in TSP-1 controlled bone turnover. In aim 1, we will use an oncogenic, immunocompetent mouse model to study the initiation of bone metastasis in androgen-independent, aggressive, metastatic prostate cancer. We will deplete or infuse mice with platelets in the presence of tumors and assess the consequences on bone structure by microcomputed tomography and histology. In addition, we will use platelet releasates from mice with and without tumors in vitro to study changes in osteoblast and osteoclast proliferation and differentiation. In aim 2, to determine the mechanism of platelet effects on bone, we will focus on TSP-1, a protein known to control tumor growth that is highly expressed in platelets. We will modulate the levels of TSP-1 in the presence and absence of tumor conditioned media or platelet releasate from tumor-bearing mice and determine the effects on bone cell proliferation and differentiation. The role of TSP-1 in vivo will be determined using TSP-1 null mice by injecting tumors and assessing the effects on bone structure. In the final aim 3, we will use our established models to study the role of TSP-1 activation of TGF-21 in tumor growth and bone remodeling in preparation for metastases. These data will provide insights to cross-talk between tumors and bone prior to metastasis. Further, our proposed research will produce pathophysiologically relevant data on the molecular mechanisms of prostate cancer induced bone remodeling. PUBLIC HEALTH RELEVANCE: Our study will investigate the mechanism of pre-metastatic communication between primary tumors and bone. The results of this investigation will identify new targets for the prevention and treatment of prostate cancer bone metastasis. In addition, these targets could be used for the screening of prostate cancer metastasis. These improvements in patient care will result in improved diagnosis, treatment, and quality of life for prostate cancer patients with bone metastases.